Pathogenic Yeasts Deploy Cell Surface Receptors to Acquire Iron in Vertebrate Hosts

Brown et al. (2012) [1] recently highlighted the growing threat that fungal pathogens pose for humans, as well as the pressing need for additional antifungal drugs and efficacious vaccines. In this context, the process of iron acquisition presents compelling opportunities to prevent or treat fungal diseases because iron is an essential nutrient for pathogen proliferation in vertebrate hosts. Fungi and other pathogens must deploy competitive uptake mechanisms to steal iron from host sources and overcome the iron sequestration associated with nutritional immunity [2]. These extracellular and surface uptake functions may provide readily accessible targets for drugs to block iron uptake, and iron transporters might also be exploited to introduce antifungal agents into fungal cells [3], [4]. Additionally, extracellular or exposed transporters may be useful vaccine targets to block iron uptake and pathogen proliferation. Mechanisms of iron acquisition have been well characterized in many microbial pathogens, and information is rapidly accumulating for fungal pathogens [5]–[9]. Fungi generally acquire iron by several mechanisms including: 1) the production and uptake of siderophores; 2) the use of a ferroxidase-iron permease complex for high-affinity uptake; 3) the transport of ferrous iron; and 4) the acquisition of iron from heme and hemoglobin [7]–[9]. Reductases in the plasma membrane and secreted reductants facilitate the reduction of ferric iron to ferrous iron for high- or low-affinity uptake [7]–[9]. The exploration of these mechanisms in fungal pathogens has revealed intriguing connections between cell surface molecules (cell wall and secreted proteins, capsular polysaccharide, and biofilms) and functions for iron acquisition from vertebrate sources (Figure 1A, B). Here we highlight these connections for the pathogenic yeasts Candida albicans and Cryptococcus neoformans. We also discuss the extent to which the newly identified functions add depth to our understanding of iron acquisition by fungi and illustrate the complex integration of iron sensing and virulence. Figure 1 Cell surface functions for iron acquisition in C. albicans and C. neoformans. Cell Surface Proteins Link the Use of Ferritin, Heme, and Hemoglobin with Biofilm Formation in C. albicans The adhesin Als3 and the CFEM domain protein Rbt5 are two notable examples of proteins that link cell surface activities related to morphogenesis and/or biofilm formation with iron acquisition in C. albicans (Figure 1C). Als3 is a hypha-specific surface protein that functions as an adhesin for epithelial and endothelial cells, and that also mediates adherence to extracellular matrix proteins (reviewed in [10]). The ability of C. albicans to switch its morphology between yeast and hyphal forms is important for virulence, as is the ability of the fungus to form biofilms on implanted medical devices. Als3 contributes to virulence in mouse models of candidiasis, although the impact of the protein depends on the method of inoculation and the immune status of the host [10]. Expression of ALS3 is transcriptionally controlled in a complex manner by regulators of the yeast-hyphal transition, by the major regulator of biofilm formation Bcr1, and by the alkaline response transcription factor Rim101 [10]–[14]. Als3 is an interesting multifunctional protein because, in addition to binding to and provoking endocytosis of the fungus by host cells, it also plays a role in biofilm formation and it binds the host iron-storage protein ferritin. Specifically, Almeida et al. (2008) [15] found that C. albicans can use ferritin as an iron source at physiological pH, and that Als3 is required for this process. Ferritin is bound by hyphal cells that express Als3 (but not by yeast cells), and deletion of the ALS3 alleles eliminates both binding and growth on ferritin. The ferritin binding by hyphae is also observed when these cells invade epithelial cells in vitro, and Als3 is required for C. albicans to damage these cells [15]. Overall, Als3 functionally links biofilm formation, the yeast-hyphal transition, and the use of a specific host iron source. The second example of the connection between biofilm formation, morphology, and C. albicans iron acquisition involves Rbt5, an O-mannosylated, glycosylphosphatidylinositol (GPI)-anchored protein (Figure 1C) [16]–[18]. Rbt5 is located in the plasma membrane and the cell wall, the protein binds heme and hemoglobin, and deletion of RBT5 reduces the use of these host iron sources by C. albicans [16]–[18]. RBT5 expression is induced by iron limitation and negatively regulated by the Tup1 regulator of morphology [17], [19]. Related genes encoding CFEM domain proteins are present in C. albicans, and these include RBT51/PGA10, CSA1, CSA2, and PGA7. Rbt51 also participates in hemoglobin binding and, in fact, the protein was originally identified in a screen for C. albicans genes that allowed S. cerevisiae to use iron from hemoglobin [17]. Weissman et al. (2008) [18] exploited this property of Rbt51 to identify mutations in S. cerevisiae that blocked hemoglobin use. The identified functions included subunits of the vacuolar ATPase, components of the ESCRT system, HOPS complex proteins and t-SNAREs, and several other functions. Notably, the ESCRT and HOPS complexes, and the t-SNAREs, contribute to endocytosis. An examination of C. albicans mutants with defects in the corresponding genes confirmed that many of these functions played roles in iron use from hemoglobin (e.g., Vma11, Vps41, ESCRT complex components, Myo5). Overall, these studies revealed an endocytic pathway for heme/hemoglobin internalization and trafficking to the vacuole for processing. Similar to Als3, mutants lacking Rbt5, Rbt51, or the related protein Csa1 form thinner and more fragile biofilms with less extracellular matrix compared with the wild-type strain [20], [21]. These mutants also displayed changes in their cell surface as examined microscopically and by measurements of cell surface hydrophobicity. Interestingly, conserved transcriptional regulation by the biofilm regulator Bcr1 is observed for three CFEM genes in C. albicans (RBT5, PGA7, and CSA1) and for three genes (CFEM2, CFEM3, and CFEM6) in the related pathogen Candida parapsilosis [22]. However, these proteins have divergent roles in that the three CFEM proteins are not involved in biofilm formation in C. parapsilosis [22].

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